The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC

Abstract

Abstract This study aimed to explore the role and mechanism of felodipine in lung cancer therapy. Murine subcutaneous lung squamous cancer (LUSC) models constructed by KLN-205 cells were utilized to assess the effect of felodipine monotherapy and in combination with the programmed cell death protein 1 antibody (PD1ab) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4ab). Immunohistochemistry analysis was subsequently applied to detect the number of CD8+ T cells and Ki67+ cells. Lastly, a series of in vitro and in vivo experiments were performed to evaluate the effects of felodipine on human LUSC cells and explore the preliminary mechanism underlying felodipine inhibition. The results revealed that felodipine monotherapy exerted a significant inhibitory effect on LUSC growth and synergistic antitumoral activity with PD1ab and CTLA4ab. Meanwhile, immunohistochemistry analysis displayed that felodipine promoted CD8+ T-cell infiltration and downregulated Ki67 expression in tumor cells. Moreover, in vitro and in vivo experiments utilizing human LUSC cells determined that felodipine impaired the proliferative and migratory abilities of cancer cells. In addition, TCGA data analysis uncovered that nuclear factor of activated T cell (NFAT1) expression was positively correlated with overall survival and disease-free survival. Finally, the cell counting kit-8 assay signaled that felodipine might suppress tumor growth by modulating NFAT1.